9-114426286-T-C

Variant names:

• chr9-114426286-T-C
• rs10817610
• NM_015404.4:c.1091A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015404.4(WHRN):​c.1091A>G​(p.His364Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00315 in 1,613,430 control chromosomes in the GnomAD database, including 139 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (70 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (69 hom.)
• Consequence: WHRN NM_015404.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.85
• Publications: 35 publications found

Genes affected

WHRN (HGNC:16361): (whirlin) This gene is thought to function in the organization and stabilization of sterocilia elongation and actin cystoskeletal assembly, based on studies of the related mouse gene. Mutations in this gene have been associated with autosomal recessive non-syndromic deafness and Usher Syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

WHRN Gene-Disease associations (from GenCC):

• Usher syndrome type 2D

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
• autosomal recessive nonsyndromic hearing loss 31

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Usher syndrome type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009325832).
• BP6: Variant 9-114426286-T-C is Benign according to our data. Variant chr9-114426286-T-C is described in ClinVar as Benign. ClinVar VariationId is 177752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0569 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015404.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	NM_015404.4	MANE Select	c.1091A>G	p.His364Arg	missense	Exon 4 of 12	NP_056219.3
	WHRN	NM_001173425.2		c.1091A>G	p.His364Arg	missense	Exon 4 of 12	NP_001166896.1
	WHRN	NM_001083885.3		c.-59A>G		5_prime_UTR	Exon 4 of 12	NP_001077354.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WHRN	ENST00000362057.4	TSL:1 MANE Select	c.1091A>G	p.His364Arg	missense	Exon 4 of 12	ENSP00000354623.3
	WHRN	ENST00000265134.10	TSL:1	c.-59A>G		5_prime_UTR	Exon 4 of 12	ENSP00000265134.6
	WHRN	ENST00000866780.1		c.1091A>G	p.His364Arg	missense	Exon 4 of 12	ENSP00000536839.1

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2571 AN: 152194 Hom.: 70 Cov.: 33

Gnomad AFR AF: 0.0589

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.00171 AC: 2500 AN: 1461118 Hom.: 69 Cov.: 30 AF XY: 0.00150 AC XY: 1090 AN XY: 726860

African (AFR) AF: 0.0608 AC: 2034 AN: 33454

American (AMR) AF: 0.00340 AC: 152 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86212

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53402

Middle Eastern (MID) AF: 0.00175 AC: 9 AN: 5148

European-Non Finnish (NFE) AF: 0.0000567 AC: 63 AN: 1112008

Other (OTH) AF: 0.00380 AC: 229 AN: 60334

GnomAD4 genome AF: 0.0169 AC: 2576 AN: 152312 Hom.: 70 Cov.: 33 AF XY: 0.0158 AC XY: 1175 AN XY: 74482

African (AFR) AF: 0.0588 AC: 2444 AN: 41566

American (AMR) AF: 0.00634 AC: 97 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68024

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

Alfa AF: 0.00609 Hom.: 39

Bravo AF: 0.0192

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0093	T
PhyloP100		5.8
Sift4G	Uncertain	0.019	D
Vest4		0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.49

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10817610; hg19: chr9-117188566;